Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. It is named after Archibald Denis Leigh, a British
neuropsychiatrist
Neuropsychiatry or Organic Psychiatry is a branch of medicine that deals with psychiatry as it relates to neurology, in an effort to understand and attribute behavior to the interaction of neurobiology and social psychology factors. Within neurop ...
who first described the condition in 1951. Normal levels of
thiamine
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...
,
thiamine monophosphate
Thiamine monophosphate is a thiamine
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or ...
, and
thiamine diphosphate
Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all liv ...
are commonly found but there is a reduced or absent level of
thiamine triphosphate
Thiamine triphosphate (ThTP) is a biomolecule found in most organisms including bacteria, fungi, plants and animals. Chemically, it is the triphosphate derivative of the vitamin thiamine.
Function
It has been proposed that ThTP has a specific ro ...
. This is thought to be caused by a blockage in the enzyme
thiamine-diphosphate kinase
In enzymology, a thiamine-diphosphate kinase is an enzyme involved in thiamine metabolism. It catalyzes the chemical reaction
:thiamine diphosphate + ATP \rightleftharpoons thiamine triphosphate + ADP
Thus, the two substrates of this enzyme are ...
, and therefore treatment in some patients would be to take thiamine triphosphate daily.
Signs and symptoms
The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years;
[ however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis.][ Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.][
Infants with the syndrome have symptoms that include ]diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
, and dysphagia
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
(trouble swallowing or sucking), leading to a failure to thrive
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
.[ Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen. Excess lactate may be seen in the ]urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
, cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
, and blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
of a person with Leigh syndrome.[
As the disease progresses, the ]muscular system
The muscular system is an organ (anatomy), organ system consisting of skeletal muscle, skeletal, smooth muscle, smooth, and cardiac muscle, cardiac muscle. It permits movement of the body, maintains posture, and circulates blood throughout the bo ...
is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
(low muscle tone
In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial muscle contraction, contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sull ...
and strength), dystonia
Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
(involuntary, sustained muscle contraction), and ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
(lack of control over movement) are often seen in people with Leigh disease. The eyes
Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conve ...
are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis
Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease.
Internal o ...
(weakness or paralysis) and nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
(involuntary eye movements).[ Slow ]saccades
A saccade ( , French for ''jerk'') is a quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction.Cassin, B. and Solomon, S. ''Dictionary of Eye Terminology''. Gainesville, Florida: Triad Publishi ...
are also sometimes seen.[ The ]heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
and lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...
(thickening of part of the heart muscle) is also sometimes found and can cause death;[ asymmetric septal hypertrophy has also been associated with Leigh syndrome.][ In children with Leigh-syndrome associated ]ventricular septal defect
A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...
s, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.[
However, ]respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
, loss of sensation in extremities caused by damage to the peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
.
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth over the body. The two distinct types of hypertrichosis are generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is restricted to a certain area. H ...
is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the ''SURF1'' gene. The protein encoded by ''SURF1'' is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC ...
.[
]
Genomics
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
(mtDNA) and over 30 genes in nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. It ...
(gene SURF1
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the ''SURF1'' gene. The protein encoded by ''SURF1'' is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC ...
and some COX
Cox may refer to:
* Cox (surname), including people with the name
Companies
* Cox Enterprises, a media and communications company
** Cox Communications, cable provider
** Cox Media Group, a company that owns television and radio stations
** ...
assembly factors) have been implicated in Leigh disease.[
Disorders of ]oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
, the process by which cells produce their main energy source of adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP), may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual. Four out of the five protein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
es involved in oxidative phosphorylation are most commonly disrupted in Leigh syndrome, either because of malformed protein or because of an error in the assembly of these complexes. Regardless of the genetic basis, it results in an inability of the complexes affected by the mutation to perform their role in oxidative phosphorylation. In the case of Leigh disease, crucial cells in the brain stem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
and basal ganglia are affected. This causes a chronic lack of energy in the cells, which leads to cell death and in turn, affects the central nervous system and inhibits motor functions. The heart and other muscles also require a lot of energy and are affected by cell death caused by chronic energy deficiencies in Leigh syndrome.[
]
Mitochondrial DNA mutations
Mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
are essential organelle
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
s in eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells. Their function is to convert the potential energy of glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
, amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s, and fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
s into adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP) in a process called oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
. Mitochondria carry their own DNA, called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of the enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s essential to the production of ATP.[
Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in ]MT-ATP6
''MT-ATP6'' (or ''ATP6'') is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6 (or subunit/chain A). This subunit belongs to the Fo complex of the large, ...
, a gene that codes for a protein in the last complex of the oxidative phosphorylation chain, ATP synthase
ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation ...
, an enzyme that directly generates ATP. Without ATP synthase, the electron transport chain will not produce any ATP.[ The most common MT-ATP6 mutation found with Leigh syndrome is a ]point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
at nucleotide 8993 that changes a thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
to a guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
. This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells. Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genes MT-ND2
MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five ...
, MT-ND3
MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five ...
, MT-ND5
MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
, MT-ND6
MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
and MT-CO1
Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that in humans is encoded by the ''MT-CO1'' gene. In other eukaryotes, the gene is called ''COX1'', ''CO1'', or ''COI''. Cytochrom ...
.
Mitochondrial DNA is passed down matrilineally in a pattern called maternal inheritance
Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent ...
— a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.[
]
Nuclear DNA mutations
Nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. It ...
comprises most of the genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
of an organism and in sexually reproducing organisms is inherited from both parents, in contrast to mitochondrial DNA's maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
pattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
, can have an affected child if that child inherits the mutant allele from both parents.[
75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, ]cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory electr ...
(COX), cause most cases of Leigh disease. Mutations in a gene called SURF1
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the ''SURF1'' gene. The protein encoded by ''SURF1'' is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC ...
(surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria.[ SURF1 is located on the long arm of ]chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...
. Another nuclear DNA mutation that causes Leigh syndrome affects another protein complex in the mitochondria, pyruvate dehydrogenase
Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.
Pyruvate dehydrogenase is us ...
, which is an enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
in the Link reaction pathway.[ Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.][
Other nuclear genes associated with Leigh syndrome are located on ]chromosome 2
Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost e ...
( BCS1L and NDUFA10); chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...
(SDHA
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the ''SDHA'' gene. This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respi ...
, NDUFS4, NDUFAF2, and NDUFA2
NADH dehydrogenase biquinone1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the ''NDUFA2'' gene. The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane an ...
); chromosome 8
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA ...
( NDUFAF6), chromosome 10
Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
(COX15
Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the ''COX15'' gene. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesi ...
); chromosome 11
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
(NDUFS3
NADH dehydrogenase biquinoneiron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the ''NDUFS3'' gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone ox ...
, NDUFS8
NADH dehydrogenase biquinoneiron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the ''NDUFS8'' gene. The NDUFS8 prot ...
, and FOXRED1
FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the ''FOXRED1'' gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in t ...
); chromosome 12
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the to ...
(NDUFA9
NADH dehydrogenase biquinone1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene. The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain), which is located i ...
and NDUFA12
NADH dehydrogenase biquinone1 alpha subcomplex subunit 12 is an enzyme that in humans is encoded by the ''NDUFA12'' gene. The NDUFA12 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane an ...
); and chromosome 19
Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosome ...
(NDUFS7
NADH dehydrogenase biquinoneiron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the ''NDUFS7'' gene. The NDUFS7 pr ...
). Many of these genes affect the first oxidative phosphorylation complex.
X-linked Leigh syndrome
Leigh syndrome can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM
Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM r ...
br>308930
. The neurological features of Leigh syndrome caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency.
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
Leigh syndrome affects male children far more often than female children because they only have one copy of the X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
. Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.[
]
French Canadian Leigh syndrome
The type of Leigh syndrome found at a much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec is caused by a mutation in the LRPPRC
Leucine-rich PPR motif-containing protein, mitochondrial is a protein that in humans is encoded by the ''LRPPRC'' gene. Transcripts ranging in size from 4.8 to 7.0 kb which result from alternative polyadenylation have been reported for this gene.
...
gene, located on the small ('p') arm of chromosome 2. Both compound heterozygosity In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it ...
and homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutations have been observed in French Canadian Leigh syndrome. This subtype of the disease was first described in 1993 in 34 children from the region, all of whom had a severe deficiency in cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory electr ...
(COX), the fourth complex in the mitochondrial electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
. Though the subunits of the protein found in affected cells were functional, they were not properly assembled. The deficiency was found to be almost complete in brain and liver tissues and substantial (approximately 50% of normal enzyme activity) in fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s (connective tissue cells) and skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
. Kidney and heart tissues were found to not have a COX deficiency.[
French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are developmentally delayed, have mildly ]dysmorphic
A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...
facial features, including hypoplasia
Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.nasal bridge
The nasal bridge is the upper, bony part of the human nose, which overlies the nasal bones.
Association with epicanthic folds
Low-rooted nasal bridges are closely associated with epicanthic folds. A lower nasal bridge is more likely to cause an ...
, chronic metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
, and hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
(decreased muscular strength). Other symptoms include tachypnea
Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing.
In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea be ...
(unusually quick breathing rate), poor sucking ability, hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
(low blood sugar), and tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
s. Severe, sudden metabolic acidosis is a common cause of mortality.[
Estimates of the rate of ]genetic carrier
A hereditary carrier (genetic carrier or just carrier), is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, ho ...
s in the Saguenay-Lac-Saint-Jean region range from 1 in 23 to 1 in 28; the number of children born with the disease has been estimated at 1 in 2063 to 1 in 2473 live births. Genealogic studies suggest that the responsible mutation was introduced to the region by early European settlers.[
]
Pathophysiology
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classifi ...
s in the brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
, basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
, cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
, and other regions of the brain. The lesions take on different forms, including areas of demyelination
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
, spongiosis
Spongiosis is mainly intercellular edema (abnormal accumulation of fluid) in the epidermis,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathologic Basis of Disease'' (7th ed.). Saunders. Page 1230. . and is characteristic of ...
, gliosis
Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, ...
, necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
, and capillary
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
proliferation.[ Demyelination is the loss of the ]myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
around the axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
s of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.[
The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of ]pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
, which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into alanine
Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side c ...
via alanine aminotransferase
Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first character ...
or converted into lactic acid by lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
; both of these substances can then build up in the body.[
]
Diagnosis
Leigh syndrome is suggested by clinical findings and confirmed with laboratory and genetic testing.[
]
Clinical findings
Dystonia, nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
, and problems with the autonomic nervous system
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...
suggest damage to the basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
and brain stem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such as hypertrichosis
Hypertrichosis is an abnormal amount of hair growth over the body. The two distinct types of hypertrichosis are generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is restricted to a certain area. H ...
and neurologically caused deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...
. Laboratory findings of lactic acidosis or acidemia and hyperalaninemia (elevated levels of alanine
Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side c ...
in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in the metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
.[
]
Differential diagnosis
Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include perinatal asphyxia
Perinatal asphyxia (also known as neonatal asphyxia or birth asphyxia) is the medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough during the birth process to cause physical harm, usually to the brain. ...
, kernicterus
Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration ...
, carbon monoxide poisoning
Carbon monoxide poisoning typically occurs from breathing in carbon monoxide (CO) at excessive levels. Symptoms are often described as "flu-like" and commonly include headache, dizziness, weakness, vomiting, chest pain, and confusion. Large e ...
, methanol toxicity
Methanol toxicity (also ''methanol poisoning'') is poisoning from methanol, characteristically via ingestion. Symptoms may include a decreased level of consciousness, poor or no coordination, hypothermia, vomiting, abdominal pain, and a specific s ...
, thiamine deficiency
Thiamine deficiency is a medical condition of low levels of thiamine (Vitamin B1). A severe and chronic form is known as beriberi. The two main types in adults are wet beriberi and dry beriberi. Wet beriberi affects the cardiovascular system, r ...
, Wilson's disease
Wilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, ...
, biotin-thiamine-responsive basal ganglia disease (BTBGD)
Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare disease that affects the nervous system, particularly the basal ganglia in the brain. It is a treatable neurometabolic disorder with autosomal recessive inheritance. First descri ...
, and some forms of encephalitis
Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, ...
. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
is not treated with phototherapy
Light therapy, also called phototherapy or bright light therapy is intentional daily exposure to direct sunlight or similar-intensity artificial light in order to treat medical disorders, especially seasonal affective disorder (SAD) and circadi ...
, the bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
can accumulate in the basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.[
]
Treatment
Succinic acid
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
has been studied, and shown effective for both Leigh syndrome, and MELAS syndrome
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD (maternally inherited diabetes and deafness, MERRF syndrome, and Leber's hereditary optic neur ...
. A high-fat, low-carbohydrate diet
Low-carbohydrate diets restrict carbohydrate consumption relative to the average diet. Foods high in carbohydrates (e.g., sugar, bread, pasta) are limited, and replaced with foods containing a higher percentage of fat and protein (e.g., meat, p ...
may be followed if a gene on the X chromosome is implicated in an individual's Leigh syndrome. Thiamine
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...
(vitamin B1) may be given if pyruvate dehydrogenase deficiency
Pyruvate dehydrogenase deficiency (also known as pyruvate dehydrogenase complex deficiency or PDCD) is a rare neurodegenerative disorders associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one ...
is known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet with sodium bicarbonate
Sodium bicarbonate (IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda, is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cation ( Na+) and a bicarbonate anion ( HCO3−) ...
(baking soda) or sodium citrate Sodium citrate may refer to any of the sodium salts of citric acid (though most commonly the third):
* Monosodium citrate
* Disodium citrate
* Trisodium citrate
The three forms of salt are collectively known by the E number E331.
Applications
F ...
, but these substances do not treat the cause of Leigh syndrome. Dichloroacetate
Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine at ...
may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance.[ ]Coenzyme Q10
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
supplements have been seen to improve symptoms in some cases.[
Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.
In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA, performed a spindle transfer mitochondrial donation technique on a mother in Mexico who was at risk of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016. However, it is not yet certain if the technique is completely reliable and safe.]
Prognosis
Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.
Epidemiology
Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.[
]
History
Leigh syndrome was first described by Denis Leigh in 1951 and distinguished from similar Wernicke's encephalopathy in 1954.[ In 1968, the disease's link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and other ]electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
proteins were not discovered until 1977.
See also
* Joseph Maraachli case
* Neuropathy, ataxia, and retinitis pigmentosa
References
Further reading
GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP
OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP
*
*
*
External links
{{Disorders of TCA and ETC
Mitochondrial diseases
Neurological disorders
Neurological disorders in children
Rare syndromes
TCA and ETC metabolism disorders